As Dean of the Faculty of Medicine at University of Toronto, he oversaw creation of the Department of Psychiatry, and development of the medical school.

Clarke first practised psychiatry at the 999 Queen Street institution in Toronto. In 1880, then took a post at the Hamilton asylum.

Dr. Clarke was a student and brother-in-law of Dr. Joseph Workman, Superintendent of the Toronto Asylum. Clarke was an early proponents of eugenics, emphasizing the importance of restrictive laws that would limit the immigration and marriage of the "mentally defective." To them, such laws seemed necessary to stem the explosive growth of state and provincial mental asylums where foreign-born patients made up more than 50 percent of the hospital population. Further, the growth of hereditarian views in science supported eugenic proposals; psychiatry's desire for greater respectability in the medical profession made eugenic "science" attractive. By 1905, Clarke had abandoned the movement, and many of the other leading psychiatrists would follow suit by the end of World War I, when it was clear that eugenic measures were not having the desired effects.

He joined his other brother-in-law, Dr. William Metcalf at the Rockwood Hospital for the Insane, the psychiatric hospital in Kingston in 1881 and began a series of reforms in the care of the insane. One of these was freeing patients from confinement. On August 13 1885 a paranoid patient attacked them both and killed Dr. Metcalfe. Dr. Clarke survived and succeeded his brother-in-law as Medical superintendent of facility. Dr. Clarke carried on in Kingston until 1905 when he succeeded Dr. Daniel Clark as superintendent of the Toronto Asylum. In 1911 he resigned from government service and was appointed superintendent of the Toronto General Hospital.

Clarke became ill in the autumn of 1923 and died in Toronto early the next year. A headline in the Toronto Sunday World of March 23 1924 read "Canada owes immeasurable debt to Dr. C.K. Clarke who helped to lift the shadow of misery and hopelessness from insane asylums". The Clarke Institute of Psychiatry in Toronto, Canada is named in his honour.

Dowbiggin IR. Keeping America Sane: Psychiatry and Eugenics in the United States and Canada, 1880-1940. ISBN 0-8014-3356-8
Greenland C. Charles Kirk Clarke A pioneer of Canadian Psychiatry 1966. University of Toronto Press
Anon. 125 Years Keeping People Healthy Kingston Psychiatric Hospital 1981, Produced by The Kingston Psychiatric Hospital